Clinical or radiographic identification of thyroid nodules requires assessment for malignancy through tissue biopsy.1,2 Typically obtained through fine needle aspiration (FNA), thyroid nodule biopsy can distinguish cancer from benign disease in approximately 65% of cases in large series and is considered essential in the workup of any thyroid nodule.1,3 Improvements in the accuracy of tissue biopsy have utilized ultrasound and a standardized pathology reporting system.4 
Efforts to extend the utility of this tissue resource are now focused primarily on molecular methods to better predict the natural history of disease and tailor patient therapy.5 Papillary thyroid cancer (PTC), comprising more than 80% of all thyroid cancer cases, has a high propensity for spread within the lymphatic system.6 However, one important limitation of current FNA assessment is that no information is provided on the metastatic potential of thyroid malignancy.3,5,7 Up to 30% of papillary thyroid carcinoma cases demonstrate lymphatic metastases which, if untreated through surgery or radioactive iodine ablation, may lead to recurrent disease in the central or lateral neck.6,8-10 Patients with metastatic or recurrent PTC often require multiple surgical resections and radioactive iodine ablative treatments with associated increased morbidity.9-12 Predicting aggressive or metastatic variants through tissue biopsy could direct surgeons to prophylactic neck dissections and guide adjuvant radioiodine therapy to decrease the risk of local and regional recurrence and improve quality-of-life.11-13 
In the drive to develop molecular techniques to make more personalized choices for patient diagnosis and therapy, a large number of studies on the mitogen-activated protein kinase (MAPK/ERK) signaling pathway have been undertaken to understand the pathogenesis of thyroid cancer.14,15 It is understood that rearrangements of tyrosine kinase genes RET/PTC and activating mutations of the BRAF or RAS commonly activate the MAPK/ERK pathway.16-18 BRAF, an isoform of a class of serine-threonine kinases, is also a potent activator of this pathway and the V600E mutation is an important and well conserved mutation in papillary thyroid cancer.17 Activating mutations of the RAS genes, namely H-/K-/N-ras, also play an important role in the pathogenesis of papillary thyroid cancer through the MAPK/ERK pathway.18,19 Other genotype-phenotype correlations have been undertaken in thyroid cancer using gene arrays to develop predictive tools based on galectin-3, cell cycle proteins and apoptotic markers.19-25 RET/PTC translocations and activating mutations of BRAF and RAS genes are considered clinically relevant markers that have been endorsed for use by the American Thyroid Association in the diagnosis of thyroid cancer when tumor cytology is indeterminate.5,25 At this time these genetic testing regimes are utilized selectively in only a few high-volume centers. While studies of diagnostic biomarkers for thyroid cancer dominate the literature, relatively few studies have examined the pathways and processes mediating lymphatic or distant spread in thyroid cancer. Research into biomarkers for lymphatic metastases reveal a number of changes in cell cycle proteins (cyclin D1), angiogenesis (vascular endothelial growth factor-VEGF), and metalloproteinases (MMP-2) but none are clinically accepted for use.26-29 
Platelet derived growth factors (PDGFs) are a family of peptides that bind to tyrosine kinase receptors (PDGF subunits α and β) and stimulate cell survival, growth, and proliferation.30 PDGF promotes the epithelial to mesenchymal transition (EMT), an important process in tumor metastases, and complements the function of VEGF in angiogenesis.30,31 
It is, therefore, desirable to provide compositions and/methods for identifying a subject with an increased likelihood of developing or having metastatic papillary thyroid cancer (PTC).
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.